xanthohumol and Leukemia--Lymphocytic--Chronic--B-Cell

Chronic lymphocytic leukemia (CLL) is an incurable disease with a natural history of increasing resistance to chemotherapy. A novel approach to overcome chemotherapy resistance may be targeting the endoplasmic reticulum (ER).. The involvement of the unfolded protein response (UPR) in the cell killing effect of xanthohumol (X) was examined in 18 patient samples.. X-induced apoptosis of CLL cells was accompanied by the induction of glucose-regulated protein of 78 kDa (GRP78) and heat-shock protein of 70 kDa (Hsp70) protein levels and by sustained phosphorylation of the eukaryotic translation initiation factor 2 (eIF2alpha), suggesting the involvement of the ER stress transducer, the double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK). The X-box-binding protein 1 (XBP1) mRNA was spliced but no clear activation of activating transcription factor 6 (ATF6) was observed. The proapoptotic outcome was further demonstrated by the up-regulation of CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), down-regulation of myeloid cell leukemia 1 (Mcl-1) and B-cell lymphoma 2 (Bcl-2), cleavage of poly-(ADP)-ribose polymerase (PARP) and processing of caspase-3, -4 and -9. Furthermore, X showed proteasome inhibitory activity.. X stimulates the proapoptotic arm of the UPR in ex vivo CLL cells, suggesting that ER stress may play an important role during X-induced apoptosis.

Topics: Activating Transcription Factor 6; Amino Acid Chloromethyl Ketones; Apoptosis; Caspase Inhibitors; Caspases; Cysteine Proteinase Inhibitors; eIF-2 Kinase; Endoplasmic Reticulum Chaperone BiP; Endoribonucleases; Flavonoids; Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Membrane Proteins; NF-kappa B; Propiophenones; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Serine-Threonine Kinases; Unfolded Protein Response

B-chronic lymphocytic leukemia (B-CLL) is an indolent lymphoid malignancy with variable prognosis. Adverse prognostic factors comprise treatment resistance, cytogenetics (11q- and 17p-), the presence of unmutated Ig genes, and the more comprehensive activation marker Zap 70. In contrast to diminished sensitivity to chemotherapy, Zap 70+ B-CLL cells retain their responsiveness to manipulation of signal transduction and monoclonals. Xanthohumol (XA) has recently been documented to have an impact on breast cancer cell growth and invasiveness in vitro. Based on these observations, lymphocytes from patients with B-CLL were cultured in the presence of XA in vitro. XA induced a dose-dependent killing of B-CLL cells at an LD(50) ((24 h)) of 24.4 +/- 6.6 microM, independent of known adverse prognostic factors including functional loss of p53. Cell death was associated with poly (ADP)-ribose polymerase cleavage and annexin V positivity, suggestive of an apoptotic mechanism. Surprisingly, p 70(S 6 K) phosphorylation was stimulated upon XA treatment. In conclusion, XA has an antitumor activity on B-CLL cells in vitro. The molecular mechanisms behind this pro-apoptotic effect deserve further investigation.

Topics: Aged; Apoptosis; B-Lymphocytes; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Female; Flavonoids; Flow Cytometry; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Poly(ADP-ribose) Polymerases; Propiophenones; Ribosomal Protein S6 Kinases, 70-kDa; Tumor Cells, Cultured